Pathogenesis and mechanisms of protease antigen-induced innate-type airway inflammation

• Project/Area Number: 23390262
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: MATSUMOTO Kenji 独立行政法人国立成育医療研究センター, その他部局等, その他 (60181765)
• Co-Investigator(Kenkyū-buntansha): SAITO Hirohisa 独立行政法人国立成育医療研究センター, 研究所免疫アレルギー研究部, 副所長 (40130166) ; NAKAE Susumu 東京大学医科学研究所システム疾患モデル研究センター, システムズバイオロジー研究分野, 准教授 (60450409) ; OOBOKI Keisuke 独立行政法人国立成育医療研究センター, 研究所免疫アレルギー研究部, 上級研究員 (80415108)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2012: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2011: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: IL-33 / プロテアーゼ / アレルギー・ぜんそく / アレルギー / 喘息 / サイトカイン / アレルゲン

Research Abstract

After inhalation of papain (mimic of allergen with protease activity), we found 1. Early reaction (1 day) with neutrophil-dominant inflammation was induced by IL-33-release via activation of non-T cells, whereas late reaction (7 days) with eosinophil-dominant inflammation was induced by IL-33-release via activation of rag-2+ cells. 2. Biphasic (6h and 72 h) IL-13 induction was observed after IL-33 release which peaks at 6h after inhalation. 3. Immune response against papain varied with gender, age and strain. These findings may help understanding the development and pathogenesis of bronchial asthma.

Research Products

• [Journal Article] Silica and Double-Stranded RNA Synergistically Induce Bronchial Epithelial Apoptosis and Airway Inflammation (2014)
  • Author(s): Unno H, Futamura K, Morita H, Kojima R, Arae K, Nakae S, Ida H, Saito H, Matsumoto K, Matsuda A
  • Journal Title: Am J Respir Cell Mol Biol Volume: (in press) Issue: 3 Pages: 344-353
  • DOI: 10.1165/rcmb.2013-0281oc
  • Peer Reviewed
• [Journal Article] Galectin-9 enhances cytokine secretion, but suppresses survival and degranulation, in human mast cell line (2014)
  • Author(s): Kojima R, Ohno T, Iikura M, Niki T, Hirashima M, Iwaya K, Tsuda H, Nonoyama S, Matsuda A, Saito H, Matsumoto K, Nakae S
  • Journal Title: PLoS ONE Volume: 9 Issue: 1 Pages: e86106-e86106
  • DOI: 10.1371/journal.pone.0086106
  • Peer Reviewed
• [Journal Article] Silica and Double-Stranded RNA Synergistically Induce Bronchial Epithelial Apoptosis and Airway Inflammation. (2014)
  • Author(s): Unno H, Futamura K, Morita H, Kojima R, Arae K, Nakae S, Ida H, Saito H, Matsumoto K, Matsuda A.
  • Journal Title: Am J Respir Cell Mol Biol. Volume: In press
  • Peer Reviewed
• [Journal Article] [Role of IL-25 and IL-33 in allergic diseases]. (2014)
  • Author(s): Morita H, Unno H, Arae K, Ohno T, Saito H, Matsumoto K, Nakae S.
  • Journal Title: Arerugi Volume: 62 Pages: 924-935
  • NAID: 110009649375
  • Peer Reviewed
• [Journal Article] GATA-1 regulates the generation and function of basophils (2013)
  • Author(s): Nei Y, Obata-Ninomiya K, Tsutsui H, Ishiwata K, Miyasaka M, Matsumoto K, Nakae S, Kanuka H, Inase N, Karasuyama H
  • Journal Title: Proc Natl Acad Sci USA Volume: 110 Issue: 46 Pages: 18620-5
  • DOI: 10.1073/pnas.1311668110
  • Peer Reviewed
• [Journal Article] IL-33, but not IL-25, is crucial for the development of house dust mite antigen-induced allergic rhinitis (2013)
  • Author(s): Nakanishi W, Yamaguchi S, Matsuda A, Suzukawa M, Shibui A, Nambu A, Kondo K, Suto H, Saito H, Matsumoto K, Yamasoba T, Nakae S
  • Journal Title: PLoS ONE Volume: 8 Issue: 10 Pages: e78099-e78099
  • DOI: 10.1371/journal.pone.0078099
  • Peer Reviewed
• [Journal Article] Role of Interleukin-33 in Innate-Type Immune Cells in Allergy (2013)
  • Author(s): Nakae S, Morita H, Ohno T, Arae K, Matsumoto K, Saito H
  • Journal Title: Allergology International Volume: 62 Issue: 1 Pages: 13-20
  • DOI: 10.2332/allergolint.13-RAI-0538
  • NAID: 130004477181
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed
• [Journal Article] Role of IL-25 and IL-33 in allergic diseases (2013)
  • Author(s): Morita H, Unno H, Arae K, Ohno T, Saito H, Matsumoto K, Nakae S
  • Journal Title: Arerugi Volume: 62 Pages: 924-35
  • NAID: 110009649375
  • Peer Reviewed
• [Journal Article] Salivary cortisol response to stress in young children with atopic dermatitis. (2013)
  • Author(s): Kojima R, Matsuda A, Nomura I, Matsubara O, Nonoyama S, Ohya Y, Saito H, Matsumoto K.
  • Journal Title: Pediatr Dermatol. Volume: 30 Issue: 1 Pages: 17-22
  • DOI: 10.1111/j.1525-1470.2012.01770.x
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• [Journal Article] Factors Associated with Steroid Phobia in Caregivers of Children with Atopic Dermatitis. (2013)
  • Author(s): Kojima R, Fujiwara T, Matsuda A, Narita M, Matsubara O, Nonoyama S, Ohya Y, Saito H, Matsumoto K.
  • Journal Title: Pediatr Dermatol. Volume: 30 Issue: 1 Pages: 29-35
  • DOI: 10.1111/j.1525-1470.2012.01808.x
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• [Journal Article] Activation of human synovial mast cells from rheumatoid arthritis or osteoarthritis patients in response to aggregated IgG through Fcγ receptor I and Fcγ receptor II. (2013)
  • Author(s): Lee H, Kashiwakura J, Matsuda A, Watanabe Y, Sakamoto-Sasaki T, Matsumoto K, Hashimoto N, Saito S, Ohmori K, Nagaoka M, Tokuhashi Y, Ra C, Okayama Y.
  • Journal Title: Arthritis Rheum. Volume: 65(1) Issue: 1 Pages: 109-19
  • DOI: 10.1002/art.37741
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• [Journal Article] Effects of diesel exhaust particles on primary cultured healthy human conjunctivalﾂepithelium. (2013)
  • Author(s): Fujishima H, Satake Y, Okada N, Kawashima S, Matsumoto K, Saito H.
  • Journal Title: Ann Allergy Asthma Immunol. Volume: 110 Issue: 1 Pages: 39-43
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• [Journal Article] Epithelial cell-derived IL-25, but not Th17 cell-derived IL-17 or IL-17F, is crucial for murine asthma. (2012)
  • Author(s): Suzukawa M, Morita H, Nambu A, Arae K,Shimura E, Shibui A, Yamaguchi S, Suzukawa K, Nakanishi W, Oboki K, Kajiwara N, Ohno T, Ishii A, Korner H, Cua DJ, Suto H,Yoshimoto T, Iwakura Y, Yamasoba T, Ohta K, Sudo K, Saito H, Okumura K, Broide DH,Matsumoto K, Nakae S.
  • Journal Title: J immunol. Volume: 189(7) Issue: 7 Pages: 3641-52
  • DOI: 10.4049/jimmunol.1200461
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• [Journal Article] Histamine-releasing factor has a proinflammatory role in mouse models of asthma and allergy (2012)
  • Author(s): Kashiwakura JC, Ando T, Matsumoto K, Kimura M, Kitaura J, Matho MH, Zajonc DM, Ozeki T, Ra C, MacDonald SM, Siraganian RP, Broide DH, Kawakami Y, Kawakami T
  • Journal Title: J Clin Invest Volume: 122 Issue: 1 Pages: 218-28
  • DOI: 10.1172/jci59072
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• [Journal Article] The alarmin interleukin-33 drives protective antiviral CD8 + T cell responses (2012)
  • Author(s): Bonilla WV, Fröhlich A, Senn K, Kallert S, Fernandez M, Johnson S, Kreutzfeldt M, Hegazy AN, Schrick C, Fallon PG, Klemenz R, Nakae S, Adler H, Merkler D, Löhning M, Pinschewer DD
  • Journal Title: Science Volume: 335(6071) Issue: 6071 Pages: 984-989
  • DOI: 10.1126/science.1215418
  • Peer Reviewed
• [Journal Article] Role of mast cells and basophils in IgE responses and in allergic airway hyperresponsiveness (2012)
  • Author(s): Sawaguchi, M.
  • Journal Title: J.Immunol. Volume: 188 Issue: 4 Pages: 1809-1818
  • DOI: 10.4049/jimmunol.1101746
  • Peer Reviewed
• [Journal Article] ST2 Requires Th2-, but Not Th17-, Type Airway Inflammation in Epicutaneously Antigen-Sensitized Mice (2012)
  • Author(s): Morita H, Arae K, Ohno T, Kajiwara N, Oboki, K, Matsuda A, Suto H, Okumura K, Sudo K, Takahashi T, Matsumoto K, Nakae, S
  • Journal Title: Allergology International Volume: 61 Issue: 2 Pages: 265-273
  • DOI: 10.2332/allergolint.11-OA-0379
  • NAID: 130004477129
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed
• [Journal Article] Anti-inflammatory effects of high-dose IgG on TNF-α-activated human coronary artery endothelial cells. (2012)
  • Author(s): Matsuda A, Morita H, Unno H, Saito H, Matsumoto K, Hirao Y, Munechika K, Abe J
  • Journal Title: Eur J Immunol. Volume: 42 Issue: 8 Pages: 2121-31
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• [Journal Article] Non-IgE-mediated gastrointestinal food allergies: distinct differences in clinical phenotype between Western countries and Japan. (2012)
  • Author(s): Nomura I, Morita H, Ohya Y, Saito H, Matsumoto K.
  • Journal Title: Curr Allergy Asthma Rep. Volume: 12 Issue: 4 Pages: 297-303
  • DOI: 10.1007/s11882-012-0272-5
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• [Journal Article] Epithelial cell-derived IL-25, but not Th17 cell-derived IL-17 or IL-17F, is crucial for murine asthma. (2012)
  • Author(s): Suzukawa M, Morita H, Nambu A, Matsumoto K, et al.
  • Journal Title: J Immunol. Volume: 189 Pages: 3641-52
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• [Journal Article] Interleukin-33 in allergy. (2012)
  • Author(s): Ohno T, Morita H, Arae K, Matsumoto K, Nakae S.
  • Journal Title: Allergy. Volume: 67 Issue: 10 Pages: 1203-14
  • DOI: 10.1111/all.12004
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• [Journal Article] Antigen-specific T-cell responses in patients with non-IgE-mediated gastrointestinal food allergy are predominantly skewed to T(H)2. (2012)
  • Author(s): Morita H, Nomura I, Orihara K, Yoshida K, Akasawa A, Tachimoto H, Ohtsuka Y, Namai Y, Futamura M, Shoda T, Matsuda A, Kamemura N, Kido H, Takahashi T, Ohya Y, Saito H, Matsumoto K.
  • Journal Title: J Allergy Clin Immunol. Volume: 131 Issue: 2 Pages: 590-2
  • DOI: 10.1016/j.jaci.2012.09.005
  • Peer Reviewed
• [Journal Article] The role of Staphylococcal enterotoxin in atopic keratoconjunctivitis and corneal ulceration. (2012)
  • Author(s): Fujishima H, Okada N, Dogru M, Baba F, Tomita M, Abe J, Matsumoto K, Saito H.
  • Journal Title: Allergy. Volume: 67 Issue: 6 Pages: 799-803
  • DOI: 10.1111/j.1398-9995.2012.02818.x
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• [Journal Article] Okumura K., Kamradt T., Saito H., Nakae S. Paracrine IL-33 stimulation enhances lipopolysaccharide-mediated macrophage (2011)
  • Author(s): Ohno T., Oboki K., Kajiwara N., Tanaka S., Ikeda M., Iikura M., Akiyama T., Inoue J., Matsumoto K., Sudo K., Azuma M.,
  • Journal Title: Plos One Volume: 6 Issue: 4 Pages: 18404-18404
  • DOI: 10.1371/journal.pone.0018404
  • Peer Reviewed
• [Journal Article] IL-33 and Airway Inflammation (2011)
  • Author(s): Oboki, K, Nakae, S, Matsumoto K, Saito, H
  • Journal Title: Allergy Asthma Immunol Res Volume: 3(2) Issue: 2 Pages: 81-8
  • DOI: 10.4168/aair.2011.3.2.81
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• [Journal Article] Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations (2011)
  • Author(s): Noguchi E, Sakamoto H, Hirota T, Ochiai K, Imoto Y, Sakashita M, Kurosaka F, Akasawa A, Yoshihara S, Kanno N, Yamada Y, Shimojo N, Kohno Y, Suzuki Y, Kang MJ, Kwon JW, Hong SJ, Inoue K, Goto Y, Yamashita F, Asada T, Hirose H, Saito I, Fujieda S, Hizawa N, Sakamoto T, Masuko H, Nakamura Y, Nomura I, Tamari M, Arinami T, Yoshida T, Saito H, Matsumoto K
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  • DOI: 10.1371/journal.pgen.1002170
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• [Journal Article] Peripheral blood mononuclear cells from patients with bronchial asthma show impaired innate immune responses to rhinovirus in vitro (2011)
  • Author(s): Iikura K, Katsunuma T, Saika S, Saito S, Ichinohe S, Ida H, Saito H, Matsumoto K
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• [Journal Article] Cimetidine Enhances Antigen-Specific IgE and Th2 Cytokine Production (2011)
  • Author(s): Arae K, Oboki, K, Ohno T, Hirata M, Nakae, S, Taguchi H, Saito, H, Nakajima T
  • Journal Title: Allergology International Volume: 60 Issue: 3 Pages: 339-344
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  • NAID: 130004723046
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• [Journal Article] Eosinophilic gastrointestinal disorders in infants : a Japanese case series (2011)
  • Author(s): Yamada Y, et al
  • Journal Title: Int Arch Allergy Immunol Volume: 155Suppl1 Issue: Suppl. 1 Pages: 40-45
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  • Peer Reviewed